Amyotrophic lateral sclerosis (ALS), parkinsonism-dementia complex (PDC), and dementia, assumed to be a single disease entity, are highly prevalent, age-related neurodegenerative disorders among the people of Guam. Characteristically all show neuronal loss in the substantia nigra and/or anterior horn cells and severe hippocampal and neocortical neurofibrillary tangle formation. The tangles are identical to those encountered in Alzheimer disease (AD). Thus, clinically and pathologically this disease shows many aspects of the three major age- related neurodegenerative disorders encountered elsewhere in the world (ALS, AD, and Parkinson disease). Contrary to what has been reported, - the disease is not disappearing. Currently over 200 cases of ALSIPDC are in the Guam Patient Registry among an atrisk population of 17,000 individuals. However, the characteristics of the epidemic have changed. Fewer cases of ALS are seen, a greater proportion of patients present with presenile dementia, and the age of onset of necrologic impairment has increased by about 10 years. These changes support an environmental hypothesis with declining exposure, but other studies strongly suggest that an inherited gene(s) defect plays a significant role in susceptibility to this disease. The most likely model is that a gene- environment-interaction is responsible for ALS/PDC and dementia. The proposed program project, using epidemiologic, genetic, pathologic, and molecular biologic approaches, address i three major issues, 1) relevant genetic and environmental risk factors, 2) the pathogenesis and development of tau pathology, and 3) the potential role of oxidative stress and mitochondrial dysfunction. An important aspect involves the recognition that many relatively young Chamorros who die without a clinical diagnosis of ALSfPDC, show neuropathologic changes typical of ALS/PDC. This suggests that they have yet to accumulate a sufficient lesion burden to show clinical symptomatology. The study of brains of such individuals provides a truly unique opportunity to identify and characterize relevant pathogenetic features which are operative in the earliest phases of the disease. The proposed research will provide critical insights into the etiology and pathogenesis of this major public health problem for the people of Guam, while also serving as a model for the study of analogous conditions seen elsewhere in the world.